Differential evolution has been shown to be an effective methodology for solving optimization problems over continuous space. In this paper, we propose an eigenvector-based crossover operator. The ...proposed operator utilizes eigenvectors of covariance matrix of individual solutions, which makes the crossover rotationally invariant. More specifically, the donor vectors during crossover are modified, by projecting each donor vector onto the eigenvector basis that provides an alternative coordinate system. The proposed operator can be applied to any crossover strategy with minimal changes. The experimental results show that the proposed operator significantly improves DE performance on a set of 54 test functions in CEC 2011, BBOB 2012, and CEC 2013 benchmark sets.
Intrinsic and acquired anti-HER2 resistance remains a major hurdle for treating HER2-positive breast cancer. Using genome-wide CRISPR/Cas9 screening in vitro and in vivo, we identify FGFR4 as an ...essential gene following anti-HER2 treatment. FGFR4 inhibition enhances susceptibility to anti-HER2 therapy in resistant breast cancer. Mechanistically, m6A-hypomethylation regulated FGFR4 phosphorylates GSK-3β and activates β-catenin/TCF4 signaling to drive anti-HER2 resistance. Notably, suppression of FGFR4 dramatically diminishes glutathione synthesis and Fe
efflux efficiency via the β-catenin/TCF4-SLC7A11/FPN1 axis, resulting in excessive ROS production and labile iron pool accumulation. Ferroptosis, a unique iron-dependent form of oxidative cell death, is triggered after FGFR4 inhibition. Experiments involving patient-derived xenografts and organoids reveals a synergistic effect of anti-FGFR4 with anti-HER2 therapy in breast cancer with either intrinsic or acquired resistance. Together, these results pinpoint a mechanism of anti-HER2 resistance and provide a strategy for overcoming resistance via FGFR4 inhibition in recalcitrant HER2-positive breast cancer.
The development of a predictive model towards site‐selective deprotometalation reactions using TMPZnCl⋅LiCl is reported (TMP=2,2,6,6‐tetramethylpiperidinyl). The pKa values of functionalized N‐, S‐, ...and O‐heterocycles, arenes, alkenes, or alkanes were calculated and compared to the experimental deprotonation sites. Large overlap (>80 %) between the calculated and empirical deprotonation sites was observed, showing that thermodynamic factors strongly govern the metalation regioselectivity. In the case of olefins, calculated frozen state energies of the deprotonated substrates allowed a more accurate prediction. Additionally, various new N‐heterocycles were analyzed and the metalation regioselectivities rationalized using the predictive model.
Metalation site prediction: The use of simple pKa calculations allowed a reliable prediction of metalation sites in various heterocycles, arenes, olefins, and alkanes, employing the mild base TMPZnCl⋅LiCl. Using this predictive model, also unexplored N‐heterocycles were investigated, and the obtained deprotonation sites rationalized readily.
PD-L1 has been widely demonstrated to contribute to failed antitumor immunity. Blockade of PD-L1 with monoclonal antibody could modulate the tumor immune environment to augment immunotherapy. PD-L1 ...expression is also detected in several types of cancer and is associated with poor prognosis. However, the prognostic role of PD-L1 in oral squamous cell carcinoma (OSCC) is still controversial. Our aim was to determine the role of PD-L1 in the prognosis of OSCC patients to identify its potential therapeutic relevance. PD-L1 immunoreactivity was analyzed by immunohistochemistry in 305 cancer specimens from primary OSCC patients. The medium follow-up time after surgery was 3.8 years (range from 0.1 to 11.1 years). The prognostic value of PD-L1 on overall survival was determined by Kaplan-Meier analysis and Cox proportional hazard models. Higher PD-L1 expression is more likely in tumor tissues of female than male OSCC patients (P = 0.0062). Patients with distant metastasis also had high PD-L1 expression (P = 0.0103). Multivariate analysis identified high PD-L1 expression as an independent risk factor in males and smokers (males: hazard ratio = 1.556, P = 0.0077; smokers: hazard ratio = 2.058, P = 0.0004). We suggest that PD-L1 expression, determined by IHC staining, could be an independent prognostic marker for OSCC patients who are male or who have a smoking habit.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A national viral hepatitis therapy program was launched in Taiwan in October 2003. This study aimed to assess the impact of the program on reduction of end‐stage liver disease (ESLD) burden. Profiles ...of national registries of households, cancers, and death certificates were used to derive incidence and mortality of ESLDs from 2000 to 2011. Age‐gender–adjusted incidence and mortality rates of hepatocellular carcinoma (HCC) and chronic liver diseases (CLDs) and cirrhosis of adults ages 30‐69 years were compared before and after launching the program using Poisson's regression models. A total of 157,570 and 61,823 patients (15%‐25% of those eligible for reimbursed treatment) received therapy for chronic hepatitis B and C, respectively, by 2011. There were 42,526 CLDs and cirrhosis deaths, 47,392 HCC deaths, and 74,832 incident HCC cases occurred in 140,814,448 person‐years from 2000 to 2011. Male gender and elder age were associated with a significantly increased risk of CLDs and cirrhosis and HCC. Mortality and incidence rates of ESLDs decreased continuously from 2000 to 2003 (before therapy program) through 2004‐2007 to 2008‐2011 in all age and gender groups. The age‐gender–adjusted rate ratio (95% confidence interval; P value) in 2008‐2011 was 0.78 (0.76‐0.80; P < 0.001) for CLDs and cirrhosis mortality, 0.76 (0.75‐0.78; P < 0.005) for HCC mortality, and 0.86 (0.85‐0.88; P < 0.005) for HCC incidence using 2000‐2003 as the reference period (rate ratio = 1.0). Conclusions: The national viral hepatitis therapy program has significantly reduced the mortality of CLDs and cirrhosis and incidence and mortality of HCC. (Hepatology 2015;61:1154–1162)
The development of new metal‐organic frameworks (MOFs) thin films is important for expanding their functions and applications. Herein, we first report a new kind of MOF thin film by using ...aggregation‐induced emission (AIE) dicarboxyl ligand through a liquid‐phase epitaxial (LPE) layer‐by‐layer (LBL) spraying method (named AIE surface‐coordinated metal‐organic frameworks thin film, AIE‐SURMOF). The obtained AIE‐SURMOF Zn4O(TPE)3 (ZnTPE) has highly growth orientation and homogeneous thin film, showing strong fluorescent property. Furthermore, by loading chiral guest in the MOF pore, the formed chiral encapsulated AIE‐SURMOF can clearly indicate obvious circularly polarized luminescence performance with glum of 0.01. This study provides new MOF thin film and new strategy for expanding function and application of MOF materials.
A new kind of metal‐organic framework (MOF) thin film were prepared by using aggregation‐induced emission (AIE) based ligand through a liquid‐phase epitaxial (LPE) layer‐by‐layer (LBL) spraying method, which is named AIE surface‐coordinated metal‐organic frameworks thin film (AIE‐SURMOF). The obtained AIE‐SURMOF has highly growth orientation and homogeneous thin film, showing strong fluorescent property. Furthermore, by loading chiral guest in the MOF pore, the formed chiral encapsulated AIE‐SURMOF can clearly indicate obvious circularly polarized luminescence performance.
Depression, a psychiatric and dysthymic disorder, severely affects the learning, work and life quality. The main pathogenesis of depression is associated with central nervous system (CNS) ...dysfunction. Taurine has been demonstrated to exert protective effects on the brain development and can improve learning ability and memory. Our study investigated the antidepressant-like effects of taurine pre-treatment by examining the changes in depression-like behavior, hormones, neurotransmitters, inflammatory factors and neurotrophic factors in the hippocampus of a chronic unpredictable mild stress (CUMS)-induced depressive rat model. Taurine was found to inhibit the decrease of sucrose consumption and prevent the deficiency of spatial memory and anxiety in rats exposed to CUMS, suggesting a preventive effect of taurine on depression-like behavior. Furthermore, the decreased levels of 5-hydroxytryptamine, dopamine, noradrenaline; the increased levels of glutamate, corticosterone; and the decreased expressions of fibroblast growth factor-2, vascular endothelial growth factor and brain derived neurotrophic factor in depressive rats were hindered by taurine pre-administration. However, tumor necrosis factor-α and interleukin-1β levels were not significantly changed by taurine. The results demonstrated that the anti-depressive effect of taurine may be involved in the regulation of hypothalamic-pituitary-adrenal (HPA) axis and the promotion of neurogenesis, neuronal survival and growth in the hippocampus.
Developing an efficient and easy‐to‐handle strategy in designing catalysts for CO2 reduction into CO by harnessing sunlight is a promising project. Here, a facile strategy was developed to design a ...Re catalyst modified with an ionic secondary coordination sphere for photoreduction of CO2 to CO by visible light. By adding ionic liquids or tuning a different ionic secondary coordination sphere, it was discovered that an outstanding optical property, other than CO2 absorption ability or the ability to dissociation of chloride anion, is the prerequisite for catalyst design. Accordingly, a novel Re catalyst, {ReBpyMe(tris(2‐hydroxyethyl)amine)(CO)3Cl}Br (Re‐THEA), was designed, screened, and resulted in a relative high quantum yield (up to 34 %) for visible‐light‐induced CO2 reduction with a single‐molecule system. DFT calculations, combined with experimental outcomes, suggested the pendant ionic tris(2‐hydroxyethyl)amino (THEA) group on Re‐THEA can enhance visible‐light absorption, stabilize reaction intermediates, and suppress the Re–Re dimer formation.
CO2 Photoreduction: An ionic secondary coordination sphere on a rhenium catalyst remarkably improves catalytic efficiency, thus opening new avenues to designing highly efficient catalysts for photocatalytic CO2 reduction. DFT calculations suggest the pendant ionic tris(2‐hydroxyethyl)amino group can enhance visible‐light absorption, stabilize reaction intermediates, and suppress the Re–Re dimer formation.
Epstein-Barr virus (EBV) is associated with a range of epithelial and B cell malignancies as well as autoimmune disorders, for which there are still no specific treatments or effective vaccines. ...Here, we isolate EBV gH/gL-specific antibodies from an EBV-infected individual. One antibody, 1D8, efficiently neutralizes EBV infection of two major target cell types, B cells and epithelial cells. In humanized mice, 1D8 provides protection against a high-dose EBV challenge by substantially reducing viral loads and associated tumor burden. Crystal structure analysis reveals that 1D8 binds to a key vulnerable interface between the D-I/D-II domains of the viral gH/gL protein, especially the D-II of the gH, thereby interfering with the gH/gL-mediated membrane fusion and binding to target cells. Overall, we identify a potent and protective neutralizing antibody capable of reducing the EBV load. The novel vulnerable site represents an attractive target that is potentially important for antibody and vaccine intervention against EBV infection.
•Fe and O codopants substantially accelerated the electron transfer of g-C3N4 for PMS activation.•Efficient BPA removal was achieved at high salinity and within wider pH ranges.•High-valent iron-oxo ...species and singlet oxygen were identified as two main reactive species.•Nonradical pathways were elucidated based on experimental and theoretical analyses.
Peroxymonosulfate (PMS)-based advanced oxidation processes (AOPs) for wastewater treatment have recently attracted widespread interests. However, the degradation of organic pollutants via traditional radical-dominated pathway is severely limited by the side reactions between radicals and the co-existing inorganic anions, especially under high salinity conditions. Herein, an efficient Fe/O co-doped g-C3N4nanosheet catalyst was synthesized to dominantly activate PMS through a dual non-radical pathway with the singlet oxygen and high-valent iron-oxo species (Fe(V)=O). The rapid degradation of model pollutant bisphenol A (BPA) was achieved by dosing PMS (1 mM), catalyst (0.1 g/L) in a simulated high-salt wastewater (≥200 mM) of the developed Fe/O-doped g-C3N4+PMS system with a reaction rate constant of 1204-fold higher than that in g-C3N4+PMS system. The O and Fe co-dopants could reconfigurate the electronic structure of pristine g-C3N4 to produce more non-radical active species. The formed Fe(V)=O played a main role in the BPA degradation by promoting electron transfer from BPA molecule to the “metastable PMS/catalyst complex”, which was verified by electrochemical tests and density functional theory calculations. The auxiliary transient productions of ·OH+SO4·– species were also favorable for the pollutant degradation. Excellent reusability in a wide pH range confirmed the practical application prospects of the Fe/O-doped g-C3N4+PMS system. The successive addition of PMS with a low dosage into the system rich in pollutants was confirmed to favor the PMS utilization. Our work unveils the potential applications of a non-radical dominated process for the decontamination of organic pollutants in saline water.
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